title: Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells.
abstract: Increases in Rap activity have been associated with tumor progression. Although activating mutations in Rap have not been described, downregulation of Rap1GAP is frequent in human tumors including thyroid carcinomas. In this study, we explored whether endogenous Rap1GAP expression could be restored to thyroid tumor cells. The effects of deacetylase inhibitors and a demethylating agent, individually and in combination, were examined in four differentiated and six anaplastic thyroid carcinoma (ATC) cell lines. Treatment with the structurally distinct histone deacetylase (HDAC) inhibitors, sodium butyrate and trichostatin A, increased Rap1GAP expression in all the differentiated thyroid carcinoma cell lines and in four of the six ATC cell lines. The demethylating agent, 5-aza-deoxycytidine, restored Rap1GAP expression in one anaplastic cell line and enhanced the effects of HDAC inhibitors in a second anaplastic cell line. Western blotting indicated that Rap2 was highly expressed in human thyroid cancer cells. Importantly, treatment with HDAC inhibitors impaired Rap2 activity in both differentiated and anaplastic tumor cell lines. The mechanism through which Rap activity is repressed appears to entail effects on the expression of multiple Rap regulators, including RapGEFs and RapGAPs. These results suggest that HDAC inhibitors may provide a tractable approach to impair Rap activity in human tumor cells.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, 19104 Pennsylvania, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Dong
authors.forename: Christopher
authors.initials: C
authors.lastname: Korch
authors.forename: Judy L
authors.initials: JL
authors.lastname: Meinkoth
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000378:metabolism / Q000473:pathology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D020690:GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects; D020668:rap GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D020827:rap1 GTP-Binding Proteins / Q000037:antagonists & inhibitors*
chemical_list: D002087:Butyrates; D020690:GTPase-Activating Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; C484658:RAP1GAP protein, human; D034741:RNA, Small Interfering; C012589:trichostatin A; D000077209:Decitabine; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D001374:Azacitidine